Review of Stroke Therapies in the Past, Present & Future

Monday, August 1, 2011
Jason Bowman, MS, LP, CCEMT-P

Stroke is the third leading cause of death and the leading cause of disability in the U.S. Roughly one American suffers from a stroke every minute, and one dies of stroke every 3.5 minutes.1 These are powerful facts, yet prehospital treatment of stroke is virtually non-existent. Even in-hospital treatments are poorly defined and implemented in most communities.

Tissue-type plasminogen activator (tPA) is the only pharmacological treatment approved for acute ischemic strokes, but it’s administered to less than 5% of the patients.1 Even with tPA, we must treat an average of eight patients to get one who regains full function within three months. Unfortunately, of those eight patients, half will remain severely disabled or die in that same
time frame.2

One of the guiding factors in stroke treatment is that time is of the essence: The earlier treatment can be initiated, the better the outcome.3 Prehospital providers see the patient first, so their ability to diagnose strokes in the field and act quickly may play the biggest role in the survivability of the stroke patient.4

It’s already been proven that notification of a “code stroke” by paramedics reduces door-to-computed tomography (CT) time and doubles the chances that the patient will receive tPA.5 But what else can be done? What other assessment tools and treatments are available? Are there projects on the horizon to help reduce the gap between stroke patients and stroke survivors?

Pharmaceutical Intervention
In 1996, the U.S. Food and Drug Administration (FDA) approved the use of tPA for the treatment of acute strokes with less than a three-hour onset. Prior to this, there was virtually no treatment for the disease; providers had to simply wait and see. The next major advancement occurred in 2009 when this window was pushed back to 4.5 hours at the urging of the American Stroke Association.6

Although many types of fibrinolytics (clot busters), such as streptokinase, urokinase and tenecteplase, have been investigated for possible treatment, no major statistical benefits have been found to any agent; tPA remains the only treatment that’s FDA approved.

A patient must fall into certain guidelines to receive tPA, and outside of them, patients are offered virtually no direct treatment and are generally admitted to a neurological ICU for monitoring.7 But the problems with clot busters don’t simply lie in the exclusion criteria.

Of the patients who receive tPA, only one in eight will fully regain function in a three-month period, and half will die or remain severely disabled in that same time frame.2 And this is with treatment. The treatment itself is fairly simple: just give the first 10% of tPA immediately followed by the remaining 90% over the next hour. It’s generally given in the emergency department (ED), and in a very few circumstances, it’s given in ambulances; however, the prehospital use of clot busters is almost exclusively for heart attack, not stroke.8

To improve the results with clot busters, some physicians have begun treatment with intra-arterial administration of tPA. However, this is no longer a procedure that can be done in the ED, much less an ambulance. It also requires special equipment, such as special CT tables added to an angiography suite or catheterization lab to help guide the wires into the complex blood vessels of the brain. The physicians who perform these procedures are generally neurointerventionalists or interventional radiologists—not physicians found at every hospital, even all the big ones. Intra-arterial tPA is such a specific procedure that it’s generally given along with another specialized procedure: mechanical thrombectomy.

Mechanical Thrombectomy
Mechanical thrombectomy, the physical removal of a clot, has become the holy grail of stroke treatments in some regions. This is probably due to how abysmal tPA actually is in treating strokes. Unfortunately, mechanical thrombectomy has plenty of limitations as well and isn’t quite the saving grace that most paramedics—and other healthcare providers, for that matter—think it to be. The first problem we have is finding a hospital that provides mechanical thrombectomy as a service. Unfortunately, this isn’t quite as easy as it may sound.

One of the more recent trends in stroke therapy has been to create primary stroke centers (PSCs) so that EMS systems will know which centers are appropriate for stroke patients. For a facility to be a PSC, it must have a CT scanner, laboratory services available 24 hours a day, seven days a week, and written stroke protocols. The problem is that being a PSC doesn’t guarantee anything in the way of extra capabilities.

However, these protocols can vary, and they generally mandate only that a patient receives labs, CT and neurological consult within a certain period of time. No treatment mandates exist. Even in a PSC, a patient may meet all the criteria to receive tPA, but they might not get the medication in time due to certain circumstances. Also, being a PSC doesn’t guarantee the facility has the ability to perform mechanical thrombectomy. That’s generally left to comprehensive stroke centers.

Because advanced stroke care is in its infancy, EMS providers sometimes run into some strange situations, such as a comprehensive stroke center with physicians that are capable but facilities that only meet the bare minimum. Therefore, the physicians are reluctant to perform the procedure. Or they may have facilities that are capable but physicians who are unwilling or under-trained in the advanced procedures required to perform mechanical thrombectomy.

The most unfortunate part of this problem is that these two facilities could be across the street from each other. The result could be a community that’s home to two stroke centers—one with the skilled doctors, and one with the special machines, but neither with both ingredients.

So EMS systems are faced with a challenging problem. From paramedic school, providers are charged with the responsibility of being the patient’s advocate. We’re trained to diagnose and treat illness and injury in the field while transporting patients to the most appropriate receiving facility. But that’s where the catch is: Do we transport the patient to a local hospital that’s capable of providing tPA immediately, or do we bypass it to take them to a comprehensive stroke center that may or may not be able to provide any more treatment to the patient? And we make this decision knowing that every minute eats away at that four-hour clock—not from when 9-1-1 was called, but from when the patient first started having symptoms.

Some services have worked on this problem with the approach of taking Level 1 strokes (onset less than three hours) to the closest stroke-ready center, which could be a secondary or even tertiary stroke center. They take Level 2 strokes (onset greater than three hours) to the primary and comprehensive centers where there may still be treatment options available for them. But many more services have just adopted a simple approach: Take all strokes to one place.

But how well does mechanical thrombectomy actually work? And is it worth going through all of this trouble? A simple answer would be yes, it’s better than tPA—significantly so. It can even be used outside of the four-hour window. But unfortunately, it’s nowhere near what it’s made out to be, nor is it as simple as placing cardiac stents in the brain. Several different devices are on the market, but only the MERCI and Penumbra systems currently have FDA approval.

The MERCI device is designed to “corkscrew” into the clot and retract into a sheath that can then be retrieved. The Penumbra device involves a pick and a suction tube that picks away pieces of the clot that are then sucked out. In recent clinical trials, the MERCI device showed 55% recanalization (re-opening of the artery) rates with 36% favorable outcomes; unfortunately, 34% of patients died, and 9% suffered intracerebral hemorrhage (brain bleed).

The Penumbra device was shown to have 81% recanalization rates; however, downstream emboli were not uncommon.9 There’s also a promising new device being tested for the market, called the EKOS, that delivers ultrasound waves directly to the clot to help deliver intra-arterial tPA deeper into the clot.9 But how does ultrasound play a role in stroke therapy?

Diagnostic Ultrasound in Stroke Therapy
Ultrasound use is an area where EMS may be able to make a significant difference in stroke assessment and care. The use of ultrasound in stroke therapy is a relatively new practice. In 1981, Rune Aaslid, MD, created the first Transcranial Doppler machine (TCD), the “UrDoppler” at the then new vascular laboratory of the Neurosurgical Department of Inselspital in Bern, Switzerland. It’s still in use today. With the recent advent of cheaper, smaller and more user friendly machines, TCD is becoming more commonplace.

Although a CT scan is a powerful tool to detect the presence of bleeding in the brain, it’s limited in its ability to detect a blood clot. The opposite could be said of TCD: Although it’s unable to easily detect a head bleed, it’s readily able to find a clot. TCD was recently compared to CTA (a special type of CT with contrast) and found to have an overall accuracy of 89.4% in detecting embolic stroke, the most common type of stroke.8 When diagnosing stroke, it’s important to rule out a hemorrhagic stroke (head bleed) before administering clot busters because this could cause the patient to bleed out and die.

There are only two major types of stroke, embolic and hemorrhagic. The presentation of a patient with both embolic and hemorrhagic stroke is extremely rare. So if you can rule out one, then you can generally rule in the other.10 In essence, the diagnosis of the occlusion of a cerebral artery via TCD could possibly be enough evidence to allow for the administration of tPA in the prehospital environment. But that would mean paramedics would have to perform TCD in the field.

Advent of Ultrasound for Acute Stroke
In 2008, a neurologist named Thilo Hoelscher, MD, deployed a Sonosite Micromaxx ultrasound device in an air medical unit in Germany. TCD was performed in the patient’s home or in the helicopter prior to or during transport. The average time of the exam was around two minutes, and adequate images were obtained of the middle cerebral artery (MCA). The MCA is most important not only because it’s the easiest to find by TCD, but it’s also the site of approximately 70% of all strokes.11

By limiting the exam to one easy-to-find vessel, Hoelscher turned a difficult scanning technique into one that could be taught to an EMT-B. After a review of some of Hoelscher’s work, Keller (Texas) Fire-Rescue (KFR) started a limited-trial use of TCD in the field. Within a matter of weeks, two patients were scanned. The procedure was included in the department-wide rollout of expanded scope prehospital ultrasound in November 2010. As of July 2011, KFR has partnered with Texas Health Resources Fort Worth, a regional stroke center, to begin a randomized clinical trial to investigate the reduction in door to tPA times by field diagnosis of stroke via TCD.

Hoelscher is currently focusing on the use of diagnostic level ultrasound to destroy blood clots in the brain. This discovery came about from several articles about improved clot busting rates using ultrasound and tPA, and even greater clot busting rates with ultrasound, tPA and an ultrasound contrast agent called microbubbles.12 The prevailing thought was that the ultrasound waves were driving the tPA molecules deeper into the clot, but Hoelscher believed the ultrasound energy itself was destroying the clot. Several studies later prove he was correct.

Clot weight-loss studies show that ultrasound alone causes more clot destruction than the control.8 By combining ultrasound with an ultrasound contrast agent, clot weight loss vs. control was the same as ultrasound with tPA. According to Hoelscher, an ultrasound contrast agent isn’t a dye as used in radiologic examinations; it’s actually an injection of billions of extremely tiny bubbles, smaller than a red blood cell. After they’re struck with ultrasonic energy, the bubbles vibrate and burst, which leads to enhanced definition of the image.

He believes that when the bubbles burst near the clot, they act like little bombs, helping destroy the clot cell by cell. He took this evidence further. During a routine visit to an ED, he came across a stroke patient who was outside the window of treatment with tPA. The patient had suffered an occlusion of the left MCA.

At that moment, the patient wasn’t a candidate for any treatment and was destined for transfer to the neurological ICU for monitoring. Hoelscher convinced the ED physician to let him try his therapy and obtained approval from the patient’s family. After injecting the patient with ultrasound contrast, he visualized the clot with TCD for 30 minutes.

After 30 minutes, the vessel had reopened, and the clot was beginning to dissolve on its own. The patient eventually regained full function. Obviously, this is only one example, but it’s a powerful one.8

Hoelscher is also currently working on animal studies to further prove the efficacy and safety of diagnostic grade sonothrombolysis (clot busting with ultrasound). It’s a simple procedure of inducing clots in the renal arteries of rabbits, placing a human temporal bone over the site and letting it work for 30 minutes to determine whether the artery has reopened. So far the results have been promising, and with the work already starting in Keller, human trials are hopefully not too far down the road.

However, Hoelscher isn’t content with just diagnostic-grade ultrasound; he has another project looming on the distant horizon: high-intensity focused ultrasound (HIFU). HIFU is basically like placing about 3,000 diagnostic-grade probes evenly around the skull, localizing the clot and destroying it in seconds with a focused ball of sonic energy.

This may sound far-fetched, but HIFU is already FDA approved to non-invasively destroy certain types of tumors.13 Although this type of advancement is probably far into the future, envision what it would be like to eventually place probes onto a patient’s head with a handful of stickers similar to ECG electrodes, finding the clot and zapping it right there in the patient’s living room.

Conclusion
Stroke is one of the least treatable of all common medical conditions patients and EMS providers face. Currently, EMS is limited in its ability to treat these patients, and hospitals are only able to do slightly more. Even the gold standard of tPA is greatly lacking in actual ability to produce positive results. But as always, we’re on the cusp of innovation. Mechanical thrombectomy and intra-arterially injected tPA are already here; they just need a little more refinement and a little more time to get operational in every community.

And the future looks bright as well. Eventually, advanced EMS systems may be able to start treatment in the ambulance and continue it into the stroke centers, where further treatment can be obtained. Perhaps one day, stroke care will be as simple as Hoelscher envisions. Until then, EMS services everywhere will be standing by, ready to give their patients the most cutting-edge treatments technology can provide. JEMS

This article originally appeared in August 2011 JEMS as “Conquering Clots: Diagnostic use of ultrasound in stroke treatment.”

Differences between Aspirin, Coumadin & tPAAspirin: When an injury occurs to a blood vessel, chemicals are released that cause platelets to become sticky and aggregate on the injury. Aspirin inhibits this process and therefore stops a clot from growing any larger. This class of drug is called an antiplatelet.

Coumadin: Multiple chemicals are required to continue this so-called “clotting cascade,” and several are formed by reactions with vitamin K. Coumadin works by inhibiting vitamin K’s participation in those reactions, thus reducing the levels of critical clotting enzymes. This is called an anticoagulant and simply makes it harder for clots to form.

tPA: During the final stages of clot formation, little molecules of plasmin are trapped inside the structure of the clot. Then, they’re wrapped in a protective net called fibrin. When the wound under the clot is healed and the body no longer needs it, tPA is released. This activates the trapped plasmin, which breaks the fibrin net and causes the clot to self-destruct. In strokes, pharmaceutical grade tPA is administered in high doses to cause this same clot busting reaction. This is called a fibrinolytic and is the only method of destroying a clot that has already formed.